This resubmission is comprised of three applications (Clinical and Data Coordinating Centers (CCC, DCC) and Cost-Effectiveness Analysis Core). We propose to conduct a large (N=2100) simple, superiority trial in the US and Canada - BEST - comparing best open surgery to best endovascular revascularization to prevent mortality, limb-amputation or further revascularization in a target limb with critical limb ischemia (CLI), meeting the current mandate for assessing comparative effectiveness. Trial leadership is comprised of a closely integrated and highly experienced group of investigators based at a CCC (Brigham and Women's Hospital, BWH , Boston University Medical Center, BUMC, and Massachusetts Hospital, MGH, Boston, MA), a DCC (New England Research Institutes, Inc., Watertown, MA) and an Executive Committee of experts in the field. The Health Economics Group at BWH will work closely with the DCC to address assessment of quality of life and cost-effectiveness (C-E). The trial will be conducted at approximately 120 sites in the U.S. and Canada, builds upon prior feasibility data and endeavors to address limitations of current research in this area. Peripheral artery disease prevalence is 15-20% over 70 years, with higher rates in smokers and diabetics. In the subset with CLI, 40% require limb amputation and annual mortality exceeds 20%. With the advent of endovascular techniques for revascularization, we demonstrate from our completed surveys that there is current equipoise among practitioners with respect to best therapy in the majority of CLI cases. The BEST trial will provide, for the first time, urgently needed clinical guidance for CLI management in the context of C-E by using: a pragmatic design, including a range of established techniques; a novel primary endpoint - MALE (major adverse limb event including limb amputation or major re-intervention, bypass graft/graft revision or thrombectomy/thrombolysis) - free survival; multi-disciplinary recruitment of vascular surgeons and interventional cardiologists and radiologists; and an innovative, cost-efficient C-E approach. Additional endpoints include other clinical event rates, functional status and QOL and C-E, all using standard definitions and instruments. 140 eligible centers in North America will be approached to ensure 120 are initiated and 80 sites each recruit 1 subject/month over 27 months accrual. Trial duration is 4.25 yrs - 2.25 yrs accrual and 2.0 yrs minimum follow-up. Two cohorts will be studied: All-Vein (N=1620) and Prosthetic Conduit (N=480). Within each cohort, the trial is stratified on 2 factors (4 strata): tissue loss vs. isolated rest pain and infrainguinl with/without significant infrapopliteal occlusive disease. In the All-Vein cohort, BEST has 85% power to detect an EVT vs. OPEN hazard ratio of 1.25 in the primary endpoint (MALE-free survival) with crossover rates accounted for, as well as 2% loss to follow-up. In the Prosthetic Conduit cohort, there is 80% power to detect a hazard ratio of 0.70 for the primary endpoint. This resubmission fully addresses all prior reviewer concerns, to successfully and efficiently execute a trial that will provide important information for the CLI community. PUBLIC HEALTH RELEVANCE: With the aging of the US population and increasing diabetes, there is an increase in ischemic leg pain and open leg ulcers, frequently requiring amputation. The results of the BEST trial (including 2,100 participants in North America) will provide clinical guidance on the most cost-effective ways to reduce leg pain, heal leg ulcers and prevent disabling amputation, by testing a range of surgical and endovascular techniques. (End of Abstract)